Diseases associated with viral and retroviral infections are major medical, veterinary and agricultural problems in the United States and worldwide. Diseases of known viral origin include chicken pox, the common cold, cytomegalovirus disease (CMV), dengue fever, encephalitis, hoof-and-mouth disease, herpes infections, influenza, keratoconjunctivitis, measles, mumps, Newcastle disease, poliomyelitis, rabies, rubella, scrapie, shingles, smallpox, tick fever, West Nile Fever, and yellow fever, to name but a few. An especially serious problem at the present time is the rapid escalation in reported cases of AIDS (Acquired Immune Deficiency Syndrome), whose causative agent is strongly suspected to be HIV (Human Immunodeficiency Virus).
There are urgent and compelling reasons for the development of more efficacious and safer treatments of viral and retroviral infections. It is estimated that at least one and a half million people in the United States alone have been infected with the human immunodeficiency (HIV) or AIDS virus. HIV causes a decay of a major arm of the immune system, the immune helper cells (T4 helper or CD4.sup.+ helper cells). This decay leads to a wide spectrum of diseases, generally called HIV disease, of which AIDS is the most serious and devastating form. It is anticipated that over one third of the budget for medical care in the U.S. will be consumed on HIV disease. There is an escalating incidence of other viral diseases as well. For example, cytomegalovirus (CMV) infection is rapidly increasing in the teenage population of the United States.
We have noted that two commonly-used antioxidants and preservatives, butylated hydroxyanisole (BHA) and butylated hydroxytoluene (BHT) have been reported to have some efficacy in ameliorating some viral infections. Some of these reports are summarized below:
______________________________________ VIRUS REFERENCE ______________________________________ Newcastle Disease Brugh, M., "Chemical Regulation Virus of Immunity", in Veterinary Med., A. R. Liss, 1984, pp. 229-234; Brugh, M., Science 197: 1291 (1977); Winston, et al., Am. J. Vet. Res. 41: 391 (1980). HIV Reimund, E., Medical (HIV) Hypotheses 23: 39 (1987); Aloia, et al., PNAS 85: 900 (1988). Bacteriophage PM2 Cupp, J., et al., Antimicrobial Agents and Chemotherapy 8: 698 (1975). Pseudorabies Virus Pirtle, E. C., et al., Am. J. Vet. (PRV) Res. 47: 1892 (1986). Bacteriophage (.phi.6) Wanda, P., et al., Antimicrobial Agents and Chemotherapy 10: 96 (1976). Herpes Simplex Virus Keith, A. D., et al., Proc. Soc. (HSV-1) Exptl. Biol. & Med. 170: 237 (1982). Herpes Simplex Freeman, D. J., et al., Clin. Labialis (HSL) Pharmacol. Ther. 38: 56 (1985). Semliki Forest Virus Kim, K. S., et al., J. Infec. (SFV) Dis. 138: 91 (1985). Cytomegalovirus (CMV) Kim, K. S., et al., J. Infec. Dis. 138: 91 (1985). ______________________________________
It has been observed that certain viruses and retroviruses including, for example, cytomegalovirus (CMV), herpes simplex virus, herpes zoster virus, Epstein-Barr virus (EBV), Newcastle Disease virus, Semliki Forest virus, influenza viruses, pseudorabies virus, and human immunodeficiency virus (HIV), are of the lipid membrane variety. Further, we have hypothesized that BHT, BHA, and/or the compounds of the present invention may have some impact upon said membranes, albeit other mechanisms not presently known may be responsible for the unanticipated efficacy of the compounds of the present invention.
In addition, it has been theorized that free oxygen radicals may be involved in the pathogenesis of certain viral infections (see Oda, et al., Science 244: 974-976 (1989), and that antioxidants may have an impact upon viral or retroviral infections (see Hendler, S., "The Oxygen Breakthrough," William Morrow and Company, Inc., New York, 1989; or Hendler, S., "The Complete Guide to Anti-Aging Nutrients," Simon and Schuster, New York, 1984.)
As a result of our independent observations, we believe there might be substances possessing the ability to fluidize viral membranes, or otherwise affect their structures, in ways that make them less capable of infecting cells. It is to be expressly understood that the invention disclosed herein is not limited to or by a particular theory of operation, however.
In recent years, many investigators have proposed novel treatments for combating insidious forms of disease, many involving viruses or retroviruses as the causative agents. Due to the many differences that separate these pathogens--including, for example, their structure, their method of replication and their susceptibility to or resistance to various treatment modalities--one might not expect a single method of inhibiting the development of viral and retroviral infections o be feasible. Nevertheless, such a methodology is now available, due to the unanticipated efficacy of known and novel compounds in affecting membrane fluidity, among other things.
Therefore, in response to this pervasive need for safer and more efficacious treatments of viral and retroviral infections, and in light of our observations, we undertook to design and synthesize a variety of new molecules and to propose methods for their use, in order to further explore the relationship of structure and activity, in the hope of discovering even more highly effective antiviral substances.
The present invention also relates to methods for inhibiting viral and retroviral infections via use of known compounds with unexpected efficacy in combating viral and retroviral infections. The present invention also suggests the use of novel compounds to inhibit these infections, as well as methods for their use in living organisms.